DE1110155B - Process for the production of new basic ethers or their salts with anti-Parkinson effects - Google Patents
Process for the production of new basic ethers or their salts with anti-Parkinson effectsInfo
- Publication number
- DE1110155B DE1110155B DEB57041A DEB0057041A DE1110155B DE 1110155 B DE1110155 B DE 1110155B DE B57041 A DEB57041 A DE B57041A DE B0057041 A DEB0057041 A DE B0057041A DE 1110155 B DE1110155 B DE 1110155B
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- Germany
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- radical
- basic
- general formula
- substituted
- halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung neuer basischer Äther bzw. deren Salzen mit Antiparkinsonwirkung Zusatz zum Patent 1090 201 Gegenstand des Patents 1 090 201 ist die Herstellung neuer basischer Äther der allgemeinen Formel in welcher R1 und R2 Halogen, niedrige Alkyl-, Alkoxy- oder Alkylmercaptoreste bedeuten, wobei einer der beiden Substituenten R1 und R2 auch Wasserstoff sein kann, und A - X einen basisch substituierten, geradkettigen oder verzweigten Alkylenrest darstellt.Process for the production of new basic ethers or their salts with anti-Parkinson's effect Addition to patent 1090 201 The subject of patent 1 090 201 is the production of new basic ethers of the general formula in which R1 and R2 denote halogen, lower alkyl, alkoxy or alkyl mercapto radicals, where one of the two substituents R1 and R2 can also be hydrogen, and A - X represents a basic substituted, straight-chain or branched alkylene radical.
Das Verfahren ist dadurch gekennzeichnet, daß man in an sich bekannter Weise entweder substituierte l-Phenylcyclohexanole der allgemeinen Formel in welcher R1 und R2 die oben angegebene Bedeutung haben, mit Alkylhalogeniden der allgemeinen Formel Hal-A-Y, in welcher A einen geradkettigen oder verzweigten Alkylenrest bedeutet und Y einen organischen basischen Rest oder eine in einen basischen Rest überführbare Gruppe (Halogen, Hydroxyl) darstellt, umsetzt oder in Umkehrung dieser Reaktion substituierte l-Phenylcyclohexylhalogenide der allgemeinen Formel in welcher R1 und R2 die oben angegebene Bedeutung haben, mit Alkanolen der allgemeinen Formel HO-A-Y, in welcher A und Y die oben angegebene Bedeutung haben, umsetzt, worauf man gegebenenfalls den Rest Y in üblicher Weise in den basischen Rest X überführt und die erhaltenen basischen Äther gewünschtenfalls in üblicher Weise in Salze überführt.The process is characterized in that either substituted l-phenylcyclohexanols of the general formula are used in a manner known per se in which R1 and R2 have the meaning given above, with alkyl halides of the general formula Hal-AY, in which A denotes a straight-chain or branched alkylene radical and Y represents an organic basic radical or a group which can be converted into a basic radical (halogen, hydroxyl), converts or, in the reverse of this reaction, substituted l-phenylcyclohexyl halides of the general formula in which R1 and R2 have the meaning given above, with alkanols of the general formula HO-AY, in which A and Y have the meaning given above, is reacted, whereupon the radical Y is optionally converted into the basic radical X in the usual manner and the If desired, the basic ether obtained is converted into salts in the customary manner.
In Ausgestaltung des Verfahrens des Patents 1090201 wurde nun gefunden, daß auch Verbindungen, welche an Stelle des Cyclohexylrestes andere Cycloalkylreste tragen, interessante pharmakologische Eigenschaften besitzen. Die neuen Verbindungen dämpfen die Stammhirn-Motorik und hemmen die zentralerregende Wirkung verschiedener Pharmaka in ähnlicher Weise wie bekannte Antiparkinsonmittel, z. B. »Disipal« - Dimethylaminoäthyl - 2 - methylbenzhydryläther), während eine periphere anticholinergische Wirksamkeit nur in geringem Maße vorhanden ist. In an embodiment of the method of patent 1090201 it has now been found that also compounds which, instead of the cyclohexyl radical, have other cycloalkyl radicals have interesting pharmacological properties. The new connections dampen the brain stem motor function and inhibit the central stimulating effect of various Pharmaceuticals in a manner similar to known anti-Parkinson drugs, e.g. B. "Disipal" - Dimethylaminoethyl - 2 - methylbenzhydrylether), while a peripheral anticholinergic Effectiveness is only present to a small extent.
Gegenstand der vorliegenden Erfindung ist also die Herstellung von neuen basischen Äthern der allgemeinen Formel in welcher R einen geradkettigen Alkylenrest mit 4, 6 oder 7 Kohlenstoffatomen bedeutet, R1 und R2 Halogen, niedrige Alkyl-, Alkoxy- oder Alkylmercaptoreste vorstellen, wobei einer der beiden Substituenten R1 und R2 auch Wasserstoff sein kann, und A - X einen basisch substituierten, geradkettigen oder verzweigten Alkylenrest bedeutet.The present invention therefore relates to the preparation of new basic ethers of the general formula in which R is a straight-chain alkylene radical with 4, 6 or 7 carbon atoms, R1 and R2 represent halogen, lower alkyl, alkoxy or alkyl mercapto radicals, where one of the two substituents R1 and R2 can also be hydrogen, and A - X is a basic substituted one , straight-chain or branched alkylene radical.
Basische Substituenten des Alkylätherrestes können eine sekundäre oder tertiäre Aminogruppe, z. B. Alkyl-bzw. Dialkylaminogruppen, oder heterocyclische Reste, wie gegebenenfalls- substituierte Piperidino-, Pyrrolidino-, Morpholino- oder Piperazinreste, sein. Basic substituents of the alkyl ether radical can be secondary or tertiary amino group, e.g. B. alkyl or. Dialkylamino groups, or heterocyclic Radicals such as optionally substituted piperidino, pyrrolidino, morpholino or piperazine residues.
Die Herstellung der neuen Verbindungen erfolgt nach den für die Gewinnung basischer Äther bekanntgewordenen und im Patent 1 090 201 genannten Methoden. The production of the new connections takes place according to the for the extraction basic ether which have become known and are mentioned in patent 1,090,201.
Gegenüber den aus Arzneimittelforschung, Bd. 7, 1957, S. 725 bis 727, und aus der deutschen Patentschrift 862 446 bekannten Antiparkinsonmitteln, welche strukturell nur eine entfernte Ähnlichkeit mit den Verfahrensprodukten der vorliegenden Erfindung aufweisen, besitzen die neuen basischen Äther ein günstigeres Verhältnis zwischen zentraler und peripherer anticholinergischer Wirkung und damit eine ausgeprägte zentralanticholinergische Spezifität. Darüber hinaus zeigen die Verfahrensprodukte zusätzlich ausgeprägte zentralstimulierende Eigenschaften, welche die in Arzneimittelforschung, Bd. 7, 1957, S. 725 bis 727, und in Arch. exper. Path. u. Pharmakol., Bd. 226, 1955, S. 18 bis 33, beschriebenen Antiparkinsonmittel nicht aufweisen. Einige Vertreter der neuen basischen Äther, z. B. der [l-(p-Chlorphenyl)-cyclopentyl]-[γ-(4-methylpiperazinyl-(1))-propyl]-äther, zeichnen sich im Tierexperiment durch eine starke isolierte zentralerregende Wirkung bei gleichzeitigem Fehlen anticholinergischer Effekte aus. Auf Grund der geschilderten Eigenschaften kann man erwarten, daß bei Verabreichung der neuen Verbindungen an Menschen die üblichen Nebenwirkungen bekannter Antiparkinsonmittel nicht in Erscheinung treten. Compared to the drug research, Vol. 7, 1957, p. 725 bis 727, and anti-Parkinson drugs known from German patent specification 862 446, which structurally only bears a distant resemblance to the products of the process present invention, the new basic ethers have a cheaper one Relationship between central and peripheral anticholinergic effect and thus a pronounced central anticholinergic specificity. In addition, the Process products additionally have pronounced central stimulating properties, which those in Arzneimittelforschung, Vol. 7, 1957, pp. 725 to 727, and in Arch. exper. Path. and Pharmakol., Vol. 226, 1955, pp. 18 to 33, do not describe anti-Parkinson’s drugs exhibit. Some representatives of the new basic ethers, e.g. B. the [l- (p-chlorophenyl) -cyclopentyl] - [γ- (4-methylpiperazinyl- (1)) - propyl] -ether, are characterized in animal experiments by a strong, isolated central stimulating effect in the absence of anticholinergic effects. On the basis of the described Properties can be expected upon administration of the new compounds people the usual side effects of known anti-Parkinson drugs do not appear.
Beispiele Allgemeine Arbeitsvorschriften zur Herstellung basischer Äther von l-Arylcycloalkanolen Methode I Zu einer Suspension von 4,0 g (0,1 Mol) Natriumamid in 20 ccm Toluol (oder Benzol) läßt man bei Raumtemperatur unter intensivem Rühren eine Lösung von 0,1 Mol eines l-Arylcycloalkanols in etwa 80 ccm Toluol (oder Benzol) eintropfen. Anschließend erwärmt man das Gemisch auf 50 bis 60"C, bis die Ammoniakentwicklung beendet ist; gegebenenfalls kann zur Vervollständigung der Reaktion noch unter Rückfluß erhitzt werden. Examples General working instructions for the production of basic Ether of l-arylcycloalkanols Method I To a suspension of 4.0 g (0.1 mol) Sodium amide in 20 cc of toluene (or benzene) is left at room temperature under intense pressure Stir a solution of 0.1 mol of a 1-arylcycloalkanol in about 80 cc of toluene (or Benzene). The mixture is then heated to 50 to 60 "C until the The evolution of ammonia has ceased; optionally can be used to complete the reaction still be heated under reflux.
Nun läßt man bei Raumtemperatur unter Rühren etwa 0,11. bis 0,12 Mol eines Aminoalkylhalogenids, gelöst in der gleichen Volumenmenge Toluol (oder Benzol), zutropfen und erhitzt das Reaktionsgemisch mehrere Stunden auf den Siedepunkt des jeweiligen Lösungsmittels. Nach dem Erkalten filtriert man den Niederschlag ab, dampft das Filtrat im Vakuum ein und destilliert den Rückstand im Hochvakuum. Now about 0.11 is left at room temperature with stirring. up to 0.12 Moles of an aminoalkyl halide dissolved in the same volume of toluene (or Benzene), are added dropwise and the reaction mixture is heated to the boiling point for several hours of the respective solvent. After cooling, the precipitate is filtered off off, the filtrate is evaporated in vacuo and the residue is distilled in a high vacuum.
Methode II Zu einer Suspension von Natriumamid (0,2 bis 0,3 Mol) in 50 ccm absolutem Toluol läßt man eine Lösung von 0,1 Mol eines l-Arylcycloalkanols in etwa 100 ccm absolutem Toluol eintropfen. Anschließend wird das Gemisch 1 Stunde auf 50 bis 600 C erwärmt und gegebenenfalls bis zum Rückfluß erhitzt. Method II To a suspension of sodium amide (0.2 to 0.3 mol) A solution of 0.1 mol of an 1-arylcycloalkanol is left in 50 cc of absolute toluene drop into about 100 ccm of absolute toluene. Then the mixture is 1 hour heated to 50 to 600 C and optionally heated to reflux.
Nun trägt man bei etwa 50"C 0,1 Mol des Hydrochlorids eines Aminoalkylhalogenids ein und erwärmt die Mischung 3 Stunden zum Sieden. Nach dem Erkalten wird eventuell überschüssiges Natriumamid durch vorsichtiges Zutropfen von Alkohol-Wasser zersetzt. Die Toluolschicht wird mit etwa 30 ccm Wasser ausgeschüttelt, getrocknet und im Vakuum eingedampft. Der ölige Rückstand wird im Hochvakuum destilliert.0.1 mol of the hydrochloride of an aminoalkyl halide is now carried at about 50 "C. and heat the mixture to boiling for 3 hours. After cooling down, it may be Excess sodium amide is decomposed by carefully adding dropwise alcohol and water. The toluene layer is shaken out with about 30 ccm of water, dried and im Evaporated in vacuo. The oily residue is distilled in a high vacuum.
Methode I und II liefern im allgemeinen die gleichen Ergebnisse; bei Verbindungen mit R = (CH2)4 wendet man jedoch vorteilhafterweise Methode II an. Die erhaltenen basischen Äther können in üblicher Weise in ihre Salze, vorzugsweise die Hydrochloride, übergeführt werden. Methods I and II generally give the same results; for compounds with R = (CH2) 4, however, method II is advantageously used at. The basic ethers obtained can preferably be converted into their salts in the customary manner the hydrochlorides.
In der folgenden Tabelle sind die nach diesen Vorschriften hergestellten
Verbindungen zusammengestellt.
Claims (1)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEB57041A DE1110155B (en) | 1960-03-12 | 1960-03-12 | Process for the production of new basic ethers or their salts with anti-Parkinson effects |
CH387160A CH388303A (en) | 1959-05-02 | 1960-04-06 | Process for the production of new basic ethers |
BE590142A BE590142A (en) | 1959-05-02 | 1960-04-26 | New basic ethers and their preparation. |
FR836994A FR355M (en) | 1959-05-02 | 1960-08-29 | Medicinal product based on [1- (p-chlorophenyl) -cyclohexyl] - [γ- (4-methyl-piperazinyl-1) -propyl] -ether. |
FR836993A FR354M (en) | 1959-05-02 | 1960-08-29 | Medicinal product based on [1- (p-chlorophenyl) -cyclohexyl] - [β-diethylamino-ethyl]-ether. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEB57041A DE1110155B (en) | 1960-03-12 | 1960-03-12 | Process for the production of new basic ethers or their salts with anti-Parkinson effects |
Publications (1)
Publication Number | Publication Date |
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DE1110155B true DE1110155B (en) | 1961-07-06 |
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ID=6971547
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DEB57041A Pending DE1110155B (en) | 1959-05-02 | 1960-03-12 | Process for the production of new basic ethers or their salts with anti-Parkinson effects |
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DE (1) | DE1110155B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE862446C (en) * | 1950-02-01 | 1953-01-12 | Ciba Geigy | Process for the production of new cyclohexanols |
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1960
- 1960-03-12 DE DEB57041A patent/DE1110155B/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE862446C (en) * | 1950-02-01 | 1953-01-12 | Ciba Geigy | Process for the production of new cyclohexanols |
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